Structural basis of biological active β-amyloid conformers

β -淀粉样蛋白（Abeta）肽作为淀粉样蛋白原纤维沉积是神经退行性疾病的标志，如脑淀粉样血管病（CAA）和阿尔茨海默病（AD）。这些事件的基础是一种分子自组装反应，这种反应可以通过预先形成的淀粉样蛋白原纤维在体外进行，也可以通过在体内向阿尔茨海默氏小鼠模型中注射含有β的脑提取物来进行。越来越多的证据表明，这种作用是由β纤维引起的。β原纤维也可能在CAA中起致病作用，尽管阿尔茨海默病的神经变性可能更依赖于中间状态的毒性作用。不同体外制备的β原纤维或中间体的结构模型相互矛盾，而在患病患者体内形成的β原纤维结构尚不清楚。在这个项目中，我们将从患病的人体组织中纯化β原纤维，使其可用于高端生物物理方法，特别是电子显微镜的直接结构分析。预期的结果可能对理解神经退行性疾病的传播很重要。

The deposition of beta-amyloid (Abeta) peptide as amyloid fibrils is ahallmark of neurodegenerative conditions, such as cerebral amyloidangiopathy (CAA) and Alzheimer´s disease (AD). Underlying theseevents is a molecular self-assembly reaction that can be seeded invitro by preformed amyloid fibrils and in vivo by intracerebral injectionof Abeta-containing brain extracts into Alzheimer mouse models.Increasing evidence shows that this effect is provoked by Abeta fibril.Abeta fibrils may also play a pathogenic role in CAA, althoughneurodegeneration in AD may rather depend on the toxic effect ofintermediate states. Conflicting structural models have been obtainedfor different preparations of Abeta fibrils or intermediates in vitro, whilethe structure of Abeta fibrils formed inside a diseased patient remainunclear. In this project we will purify Abeta fibrils from diseased humantissue to make it available for direct structural analysis with high end biophysical methods, including in particular electron microscopy.Expected results may be important for understandning the spreadingof neurodegenerative diseases.